Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Notch Signaling Activates Yorkie Non-Cell Autonomously in Drosophila

In Drosophila imaginal epithelia, cells mutant for the endocytic neoplastic tumor suppressor gene vps25 stimulate nearby untransformed cells to express Drosophila Inhibitor-of-Apoptosis-Protein-1 (DIAP-1), conferring resistance to apoptosis non-cell autonomously. Here, we show that the non-cell autonomous induction of DIAP-1 is mediated by Yorkie, the conserved downstream effector of Hippo signaling. The non-cell autonomous induction of Yorkie is due to Notch signaling from vps25 mutant cells. Moreover, activated Notch in normal cells is sufficient to induce non-cell autonomous Yorkie activity in wing imaginal discs. Our data identify a novel mechanism by which Notch promotes cell survival non-cell autonomously and by which neoplastic tumor cells generate a supportive microenvironment for tumor growth

Notch inhibits Yorkie activity in Drosophila wing discs.

During development, tissues and organs must coordinate growth and patterning so they reach the right size and shape. During larval stages, a dramatic increase in size and cell number of Drosophila wing imaginal discs is controlled by the action of several signaling pathways. Complex cross-talk between these pathways also pattern these discs to specify different regions with different fates and growth potentials. We show that the Notch signaling pathway is both required and sufficient to inhibit the activity of Yorkie (Yki), the Salvador/Warts/Hippo (SWH) pathway terminal transcription activator, but only in the central regions of the wing disc, where the TEAD factor and Yki partner Scalloped (Sd) is expressed. We show that this cross-talk between the Notch and SWH pathways is mediated, at least in part, by the Notch target and Sd partner Vestigial (Vg). We propose that, by altering the ratios between Yki, Sd and Vg, Notch pathway activation restricts the effects of Yki mediated transcription, therefore contributing to define a zone of low proliferation in the central wing discs

The Nitric Oxide-Cyclic GMP Pathway Regulates FoxO and Alters Dopaminergic Neuron Survival in Drosophila

Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a Drosophila model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines Drosophila genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and Drosophila orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A Drosophila FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD

Mechanisms and mechanics of cell competition in epithelia

When fast-growing cells are confronted with slow-growing cells in a mosaic tissue, the slow-growing cells are often progressively eliminated by apoptosis through a process known as cell competition. The underlying signalling pathways remain unknown, but recent findings have shown that cell crowding within an epithelium leads to the eviction of cells from the epithelial sheet. This suggests that mechanical forces could contribute to cell elimination during cell competition

MICALs in control of the cytoskeleton, exocytosis, and cell death

MICALs form an evolutionary conserved family of multidomain signal transduction proteins characterized by a flavoprotein monooxygenase domain. MICALs are being implicated in the regulation of an increasing number of molecular and cellular processes including cytoskeletal dynamics and intracellular trafficking. Intriguingly, some of these effects are dependent on the MICAL monooxygenase enzyme and redox signaling, while other functions rely on other parts of the MICAL protein. Recent breakthroughs in our understanding of MICAL signaling identify the ability of MICALs to bind and directly modify the actin cytoskeleton, link MICALs to the docking and fusion of exocytotic vesicles, and uncover MICALs as anti-apoptotic proteins. These discoveries could lead to therapeutic advances in neural regeneration, cancer, and other diseases

The role of non-foraging nests in polydomous wood ant colonies

A colony of red wood ants can inhabit more than one spatially separated nest, in a strategy called polydomy. Some nests within these polydomous colonies have no foraging trails to aphid colonies in the canopy. In this study we identify and investigate the possible roles of non-foraging nests in polydomous colonies of the wood ant Formica lugubris. To investigate the role of non-foraging nests we: (i) monitored colonies for three years; (ii) observed the resources being transported between non-foraging nests and the rest of the colony; (iii) measured the amount of extra-nest activity around non-foraging and foraging nests. We used these datasets to investigate the extent to which non-foraging nests within polydomous colonies are acting as: part of the colony expansion process; hunting and scavenging specialists; brood-development specialists; seasonal foragers; or a selfish strategy exploiting the foraging effort of the rest of the colony. We found that, rather than having a specialised role, non-foraging nests are part of the process of colony expansion. Polydomous colonies expand by founding new nests in the area surrounding the existing nests. Nests founded near food begin foraging and become part of the colony; other nests are not founded near food sources and do not initially forage. Some of these non-foraging nests eventually begin foraging; others do not and are abandoned. This is a method of colony growth not available to colonies inhabiting a single nest, and may be an important advantage of the polydomous nesting strategy, allowing the colony to expand into profitable areas

Dynamic endothelial cell rearrangements drive developmental vessel regression

Patterning of functional blood vessel networks is achieved by pruning of superfluous connections. The cellular and molecular principles of vessel regression are poorly understood. Here we show that regression is mediated by dynamic and polarized migration of endothelial cells, representing anastomosis in reverse. Establishing and analyzing the first axial polarity map of all endothelial cells in a remodeling vascular network, we propose that balanced movement of cells maintains the primitive plexus under low shear conditions in a metastable dynamic state. We predict that flow-induced polarized migration of endothelial cells breaks symmetry and leads to stabilization of high flow/shear segments and regression of adjacent low flow/shear segments.status: publishe

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade

The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defence. The correlation between cellular nutrient/physical status and host antiviral defence is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through the transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 Lys63-linked ubiquitylation and the binding of adaptors/substrates. Accordingly, YAP/TAZ deletion/depletion or cellular conditions inactivating YAP/TAZ through Lats1/2 kinases relieve TBK1 suppression and boost antiviral responses, whereas expression of the transcriptionally inactive YAP dampens cytosolic RNA/DNA sensing and weakens the antiviral defence in cells and zebrafish. Thus, we describe a function of YAP/TAZ and the Hippo pathway in innate immunity, by linking cellular nutrient/physical status to antiviral host defence